Liu Chaoyi, Lei Dan, Min Qiang
Department of Neurosurgery, Hanyang Hospital Affiliated to Wuhan, University of Science and Technology, No.53 Moshuihu Road, Hanyang District, Wuhan, Hanyang, 430050, China.
Neurosurg Rev. 2025 Aug 26;48(1):619. doi: 10.1007/s10143-025-03764-y.
Intracerebral hemorrhage (ICH), a subtype of stroke, is associated with high incidence and disability rates. The link between inflammatory circulating proteins and ICH is still not definitively established. Our research sets out to delve into this mystery by examining the potential causal connection between 91 such proteins and ICH, employing a sophisticated two-sample Mendelian randomization approach to get to the bottom of it.
We obtained 91 SNPs associated with inflammatory circulating proteins from a genome-wide association study (GWAS). Two-sample and multivariable Mendelian randomization analyses were conducted, with inverse variance weighted (IVW) serving as the primary method to assess the relationship between exposure and outcome. To enhance the reliability of the findings, additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were employed. Cochran's Q test was used to assess the heterogeneity of the SNPs, while MR-Egger regression and MR-PRESSO were applied to evaluate the directional pleiotropy of the instrumental variables.
Univariate Mendelian randomization analysis identified a significant causal relationship between four inflammatory circulating proteins, Axin1 (odds ratio (OR): 0.77, 95% confidence intervals (CI): 0.61-0.96, P-value = 0.0239), CXCL1 (OR: 0.81, 95% CI: 0.68-0.96, P-value = 0.0190), CXCL9 (OR: 0.85, 95% CI: 0.74-0.98, P-value = 0.0256), and MCP4 (OR: 0.79, 95% CI: 0.69-0.90, P = 0.0007), and the risk of ICH. After adjusting for confounding factors such as body weight and alcohol consumption, multivariable Mendelian randomization analysis still demonstrated a significant causal relationship between these four proteins and ICH. Furthermore, after excluding hypertension as a confounder, MCP4 expression remained significantly associated with ICH. When adjusting for type 2 diabetes, both CXCL9 and MCP4 exhibited a significant causal relationship with ICH. Reverse Mendelian randomization analysis revealed a negative correlation between ICH (as the exposure) and the expression of seven inflammatory circulating proteins.
In summary, our two-sample Mendelian randomization analysis, which operates in both directions, has revealed a likely causal link between four inflammatory proteins present in circulation and the risk of ICH. Keeping track of the expression levels of these inflammatory proteins may prove beneficial for both the prevention and management of ICH.
There is a significant bidirectional causal relationship between inflammatory circulating proteins and the risk of intracerebral hemorrhage (ICH) onset. The expression levels of Axin1, CXCL1, CXCL9, and MCP4 are negatively correlated with the risk of ICH onset, suggesting that they may serve as potential important molecular targets for ICH.
脑出血（ICH）是中风的一种亚型，其发病率和致残率都很高。循环炎症蛋白与脑出血之间的联系尚未明确确立。我们的研究旨在通过采用复杂的两样本孟德尔随机化方法，研究91种此类蛋白与脑出血之间的潜在因果关系，以揭开这一谜团。
我们从全基因组关联研究（GWAS）中获得了91个与循环炎症蛋白相关的单核苷酸多态性（SNP）。进行了两样本和多变量孟德尔随机化分析，以逆方差加权（IVW）作为评估暴露与结局之间关系的主要方法。为提高研究结果的可靠性，还采用了其他方法，如MR-Egger、加权中位数、简单模式和加权模式。使用Cochran's Q检验评估SNP的异质性，同时应用MR-Egger回归和MR-PRESSO评估工具变量的定向多效性。
单变量孟德尔随机化分析确定了四种循环炎症蛋白，即轴抑制蛋白1（Axin1）（比值比（OR）：0.77，95%置信区间（CI）：0.61 - 0.96，P值 = 0.0239）、CXC趋化因子配体1（CXCL1）（OR：0.81，95% CI：0.68 - 0.96，P值 = 0.0190）、CXC趋化因子配体9（CXCL9）（OR：0.85，95% CI：0.74 - 0.98，P值 = 0.0256）和单核细胞趋化蛋白4（MCP4）（OR：0.79，95% CI：0.69 - 0.90，P = 0.0007）与脑出血风险之间存在显著因果关系。在调整体重和饮酒等混杂因素后，多变量孟德尔随机化分析仍表明这四种蛋白与脑出血之间存在显著因果关系。此外，在排除高血压作为混杂因素后，MCP4表达仍与脑出血显著相关。在调整2型糖尿病后，CXCL9和MCP4均与脑出血呈现显著因果关系。反向孟德尔随机化分析揭示了脑出血（作为暴露因素）与七种循环炎症蛋白的表达之间存在负相关。
总之，我们的双向两样本孟德尔随机化分析揭示了循环中四种炎症蛋白与脑出血风险之间可能存在因果联系。监测这些炎症蛋白的表达水平可能对脑出血的预防和管理都有益处。
循环炎症蛋白与脑出血发病风险之间存在显著的双向因果关系。Axin1、CXCL1、CXCL9和MCP4的表达水平与脑出血发病风险呈负相关，表明它们可能是脑出血潜在的重要分子靶点。
